The classical renin-angiotensin system (RAS) is an enzymatic cascade producing angiotensin II. This occurs in 2 consecutive steps catalyzed by renin and angiotensin converting enzyme (ACE). The physiologic role of RAS is more complex than simple blood pressure control. It includes a role in tissue injury. The aim of this grant application is to increase our knowledge about how ACE functions and the roles of its substrates in the control of inflammation and fibrotic diseases. This is important since a disease like pulmonary fibrosis is a serious medical problem affecting more than 200,000 patients and is responsible for over 40,000 deaths annually according to the NHLBI. Presently, there are few treatments available to prevent or reverse the progression of fibrosis. One clinically correlated and well accepted model of lung fibrosis in mice is bleomycin-induced lung fibrosis. This grant presents evidence that manipulation of the RAS may be useful in preventing bleomycin-induced injury and lung fibrosis. This proposal is to study mice with a genetic modification in ACE that eliminates the N-domain catalytic activity. These mice are called N-KO;they have reduced lung inflammation and fibrosis following bleomycin injury. My first aim is to study why this phenomenon occurs. My hypothesis is that the increased AcSDKP (an ACE substrate) concentration in the N-KO reduces inflammation because of a different inflammatory cytokine milieu and decreased oxidative damage. Increased AcSDKP concentration may also suppress TGF-[unreadable]1/Smad signal transduction and decrease fibrosis. The second aim is to manipulate AcSDKP concentration and/or ACE inhibition as a means to reduce bleomycin-induced lung injury. By increasing AcSDKP concentration or by selective N-terminus blockage of ACE in wild type mice, reduced bleomycin-induced lung injury should be observed. This aim will provide substantial preclinical characterization to enable a rationale for possible human clinical trials. PUBLIC HEALTH RELEVANCE: In the US, pulmonary fibrosis is a serious medical problem affecting more than 200,000 patients and is responsible for over 40,000 deaths annually, according to the NHLBI. The general objective of this grant application is to increase our knowledge about how ACE functions and the roles of its substrates in the control of inflammation and fibrotic diseases. The outcome of the grant application should provide substantial preclinical characterization to enable a rationale to be developed for possible human clinical trials to treat lung disease.